Neutrophil-specific expression of JAK2-V617F or CALRmut induces distinct inflammatory profiles in myeloproliferative neoplasia.

BACKGROUND: Neutrophils play a crucial role in inflammation and in the increased thrombotic risk in myeloproliferative neoplasms (MPNs). We have investigated how neutrophil-specific expression of JAK2-V617F or CALRdel re-programs the functions of neutrophils. METHODS: Ly6G-Cre JAK2-V617F and Ly6G-Cre CALRdel mice were generated. MPN parameters as blood counts, splenomegaly and bone marrow histology were compared to wild-type mice. Megakaryocyte differentiation was investigated using lineage-negative bone marrow cells upon in vitro incubation with TPO/IL-1ß. Cytokine concentrations in serum of mice were determined by Mouse Cytokine Array. IL-1α expression in various hematopoietic cell populations was determined by intracellular FACS analysis. RNA-seq to analyse gene expression of inflammatory cytokines was performed in isolated neutrophils from JAK2-V617F and CALR-mutated mice and patients. Bioenergetics of neutrophils were recorded on a Seahorse extracellular flux analyzer. Cell motility of neutrophils was monitored in vitro (time lapse microscopy), and in vivo (two-photon microscopy) upon creating an inflammatory environment. Cell adhesion to integrins, E-selectin and P-selection was investigated in-vitro. Statistical analysis was carried out using GraphPad Prism. Data are shown as mean ± SEM. Unpaired, two-tailed t-tests were applied. RESULTS: Strikingly, neutrophil-specific expression of JAK2-V617F, but not CALRdel, was sufficient to induce pro-inflammatory cytokines including IL-1 in serum of mice. RNA-seq analysis in neutrophils from JAK2-V617F mice and patients revealed a distinct inflammatory chemokine signature which was not expressed in CALR-mutant neutrophils. In addition, IL-1 response genes were significantly enriched in neutrophils of JAK2-V617F patients as compared to CALR-mutant patients. Thus, JAK2-V617F positive neutrophils, but not CALR-mutant neutrophils, are pathogenic drivers of inflammation in MPN. In line with this, expression of JAK2-V617F or CALRdel elicited a significant difference in the metabolic phenotype of neutrophils, suggesting a stronger inflammatory activity of JAK2-V617F cells. Furthermore, JAK2-V617F, but not CALRdel, induced a VLA4 integrin-mediated adhesive phenotype in neutrophils. This resulted in reduced neutrophil migration in vitro and in an inflamed vessel. This mechanism may contribute to the increased thrombotic risk of JAK2-V617F patients compared to CALR-mutant individuals. CONCLUSIONS: Taken together, our findings highlight genotype-specific differences in MPN-neutrophils that have implications for the differential pathophysiology of JAK2-V617F versus CALR-mutant disease.

Discussion on "Bayesian meta-analysis of penetrance for cancer risk" by Thanthirige Lakshika M. Ruberu, Danielle Braun, Giovanni Parmigiani, and Swati Biswas.

Ruberu et al. (2023) introduce an elegant approach to fit a complicated meta-analysis problem with diverse reporting modalities into the framework of hierarchical Bayesian inference. We discuss issues related to some of the involved parametric model assumptions.

[Functional outcomes and return to sports, work, and daily activities after revision UKA compared to primary UKA and TKA]. / Funktionelle Ergebnisse und Wiederaufnahme von Sport, Arbeit und Alltagsaktivitäten nach Revision eines Monoschlittens im Vergleich zur Primärimplantation eines Mono- und Doppelschlittens.

BACKGROUND: Unicompartmental knee arthroplasty (UKA), in addition to total knee arthroplasty (TKA), has been shown to be effective in the surgical treatment of knee osteoarthritis with appropriate patient selection. In clinical studies, it has demonstrated superior functional results with lower complication rates. In clinical practice, these advantages must be weighed against the disadvantage of an increased revision rate, especially in younger patients with sports and work activities. OBJECTIVES: The aim of this study was to compare the functional outcome as well as the time to return to daily activities, work, and sports after revision of UKA to TKA with those of primary UKA and primary TKA using a matched-pair analysis. MATERIALS AND METHODS: The study was based on a matched-pair analysis at two defined time points, always comparing 28 patients who underwent either revision of a UKA to a TKA, primary UKA, or primary TKA. Patients completed the Oxford Knee Score, UCLA score, Knee Society score, and WOMAC score during standardized follow-up. In addition, postoperative patient satisfaction and return to activities of daily living, work, and sports were recorded in a standardized manner, and a clinical examination was performed. RESULTS: The four functional scores studied showed a common trend in favor of UKA, followed by primary TKA and revision TKA. The differences between converted UKA and primary TKA were not significant. However, at 3.2 years after the last surgery, the results of the converted UKA were significantly lower than those of the primary UKA. Return to work and sports tended to occur the earliest after UKA, followed by TKA and the revision group. All groups showed a tendency to engage in low-impact sports. CONCLUSION: The functional results of revised UKA were significantly inferior to those of primary UKA based on a 3-year follow-up. Return to work, sports, and activities of daily living tended to take longer after revision than after primary implantation of either a UKA or a TKA.

Management after acute injury of the anterior cruciate ligament (ACL). Part 3: Recommendation on surgical treatment.

PURPOSE: The aim of this consensus project was to give recommendations regarding surgical treatment of the anterior cruciate ligament (ACL) injured patient. METHODS: For this consensus process, an expert, steering and rating group was formed. In an initial online meeting, the steering group, together with the expert group, formed various key topic complexes for which multiple questions were formulated. For each key topic, a structured literature search was performed by the steering group. The results of the literature review were sent to the rating group with the option to give anonymous comments until a final consensus voting was performed. Sufficient consensus was defined as 80% agreement. RESULTS: During this consensus process, 30 topics regarding the surgical management and technique of ACL reconstruction were identified. The literature search for each key question resulted in 30 final statements. Of these 30 final statements, all achieved consensus. CONCLUSIONS: This consensus process has shown that surgical treatment of ACL injury is a complex process. Various surgical factors influence patient outcomes. The proposed treatment algorithm can be used as a decision aid for the surgeon. LEVEL OF EVIDENCE: Level V.

Synthesis and Characterization of Iron Bispyridine Bisdicyanamide, Fe[C5H5N]2[N(CN)2]2.

Fe[C5H5N]2[N(CN)2]2 (1) was synthesized from a reaction of stoichiometric amounts of NaN(CN)2 and FeCl2·4H2O in a methanol/pyridine solution. Single-crystal and powder diffraction show that 1 crystallizes in the monoclinic space group I2/m (no. 12), different from Mn[C5H5N]2[N(CN)2]2 (P21/c, no. 14) due to tilted pyridine rings, with a = 7.453(7) Å, b = 13.167(13) Å, c = 8.522(6) Å, ß = 114.98(6)° and Z = 2. ATR-IR, AAS, and CHN measurements confirm the presence of dicyanamide and pyridine. Thermogravimetric analysis shows that π-stacking interactions of the pyridine rings play an important role in structural stabilization. Based on DFT-optimized structures, a chemical bonding analysis was performed using a local-orbital framework by projection from a plane-wave basis. The resulting bond orders and atomic charges are in good agreement with the expectations based on the structure analysis. SQUID magnetic susceptibility measurements show a high-spin state FeII compound with predominantly antiferromagnetic exchange interactions at lower temperatures.

Etiology, Classification, Diagnostics, and Conservative Management of Osteochondral Lesions of the Talus. 2023 Recommendations of the Working Group "Clinical Tissue Regeneration" of the German Society of Orthopedics and Traumatology.

METHODS: Peer-reviewed literature was analyzed regarding different topics relevant to osteochondral lesions of the talus (OLTs) treatment. This process concluded with a statement for each topic reflecting the best scientific evidence available for a particular diagnostic or therapeutic concept, including the grade of recommendation. Besides the scientific evidence, all group members rated the statements to identify possible gaps between literature and current clinical practice. CONCLUSION: In patients with minimal symptoms, OLT progression to ankle osteoarthritis is unlikely. Risk factors for progression are the depth of the lesion on MRI, subchondral cyst formation, and the extent of bone marrow edema. Conservative management is the adaptation of activities to the performance of the ankle joint. A follow-up imaging after 12 months helps not to miss any progression. It is impossible to estimate the probability of success of conservative management from initial symptoms and imaging. Cast immobilization is an option in OLTs in children, with a success rate of approximately 50%, although complete healing, estimated from imaging, is rare. In adults, improvement by conservative management ranges between 45% and 59%. Rest and restrictions for sports activities seem to be more successful than immobilization. Intra-articular injections of hyaluronic acid and platelet-rich plasma can improve pain and functional scores for more than 6 months. If 3 months of conservative management does not improve symptoms, surgery can be recommended.

On the atomistic origin of the polymorphism and the dielectric physical properties of beryllium oxide.

Polymorphic beryllium oxide has been theoretically investigated from first principles as regards orbital occupancies, chemical bonding, polarization, as well as dielectric properties. By means of Crystal-Orbital Bond Index (COBI) analysis, the important role of the 2p orbitals on beryllium has been elucidated, in particular in terms of the correlation between polarization and beryllium-atom displacement, including the impact of the latter on the covalency of the BeO bond. In addition, several structural possibilities for a Bex Mg1-x O solid solution have been investigated for a Be content between 6% and 22%; for those, dynamically stable structures have been found, displaying large polarization values, more covalent BeO bonds, and a tendency for tetrahedral Be coordination. The dynamically unstable structures, however, resemble rock-salt BeO in their local structural properties around the Be atom. High dielectric constants and band gaps indicating insulating behavior have been found for those.

The Effect of Smoking on the Outcome of Matrix-Based Autologous Chondrocyte Implantation: Data from the German Cartilage Registry.

Smoking is known to have various deleterious effects on health. However, it is not clear whether smoking negatively affects the postoperative outcome following matrix-based autologous cartilage implantation (MACI) in the knee. The purpose of this study was to evaluate the effect of smoking on the outcome of MACI in the knee. A total of 281 patients receiving MACI in the knee between 2015 and 2018 were registered in the German Cartilage Database. The cohort was divided into ex-smokers, smokers, and nonsmokers. Data regarding the Knee Injury and Osteoarthritis Outcome Score (KOOS), the numeric rating scale (NRS) for pain, and satisfaction with the outcome were analyzed and compared. Follow-ups were performed at 6, 12, and 24 months after surgery. Of the 281 patients, 225 (80.1%) were nonsmokers, 43 (15.3%) were smokers, and 13 (4.6%) were ex-smokers. The three groups were comparable with respect to age, sex, body mass index (BMI), height, defect size, the need for additional reconstruction of the subchondral bone defect, number of previous knee surgeries, and defect location. However, nonsmokers had a significantly lower weight as compared with smokers. Besides a significantly lower preoperative NRS of nonsmokers as compared with smokers, there were no significant differences between the three groups with respect to KOOS, NRS, and satisfaction at 6, 12, and 24 months of follow-ups. The present study of data retrieved from the German Cartilage Registry suggests that the smoking status does not influence the outcome of MACI in the knee.

Empfehlungen der AG Klinische Geweberegeneration zur Behandlung von Knorpelschäden am Kniegelenk. / Empfehlungen der AG Klinische Geweberegeneration zur Behandlung von Knorpelschäden am Kniegelenk.

The Working Group of the German Orthopedic and Trauma Society (DGOU) on Tissue Regeneration has published recommendations on the indication of different surgical approaches for treatment of full-thickness cartilage defects in the knee joint in 2004, 2013 and 2016. Based upon new scientific knowledge and new developments, this recommendation is an update based upon the best clinical evidence available. In addition to prospective randomised controlled clinical trials, this also includes studies with a lower level of evidence. In the absence of evidence, the decision is based on a consensus process within the members of the working group.The principle of making decision dependent on defect size has not been changed in the new recommendation either. The indication for arthroscopic microfracturing has been reduced up to a defect size of 2 cm2 maximum, while autologous chondrocyte implantation is the method of choice for larger cartilage defects. Additionally, matrix-augmented bone marrow stimulation (mBMS) has been included in the recommendation for defects ranging from 1 to 4.5 cm2. For the treatment of smaller osteochondral defects, in addition to osteochondral transplantation (OCT), mBMS is also recommended. For larger defects, matrix-augmented autologous chondrocyte implantation (mACI/mACT) in combination with augmentation of the subchondral bone is recommended.

Management after acute rupture of the anterior cruciate ligament (ACL). Part 1: ACL reconstruction has a protective effect on secondary meniscus and cartilage lesions.

PURPOSE: The aim of this consensus project was to validate which endogenous and exogenous factors contribute to the development of post-traumatic osteoarthritis and to what extent ACL (anterior cruciate ligament) reconstruction can prevent secondary damage to the knee joint. Based on these findings, an algorithm for the management after ACL rupture should be established. METHODS: The consensus project was initiated by the Ligament Injuries Committee of the German Knee Society (Deutsche Kniegesellschaft, DKG). A modified Delphi process was used to answer scientific questions. This process was based on key topic complexes previously formed during an initial face-to-face meeting of the steering group with the expert group. For each key topic, a comprehensive review of available literature was performed by the steering group. The results of the literature review were sent to the rating group with the option to give anonymous comments until a final consensus voting was performed. Consensus was defined a-priori as eighty percent agreement. RESULTS: Of the 17 final statements, 15 achieved consensus, and 2 have not reached consensus. Results of the consensus were summarized in an algorithm for the management after ACL rupture (infographic/Fig. 2). CONCLUSION: This consensus process has shown that the development of post-traumatic osteoarthritis is a complex multifactorial process. Exogenous (primary and secondary meniscus lesions) and endogenous factors (varus deformity) play a decisive role. Due to the complex interplay of these factors, an ACL reconstruction cannot always halt post-traumatic osteoarthritis of the knee. However, there is evidence that ACL reconstruction can prevent secondary joint damage such as meniscus lesions and that the success of meniscus repair is higher with simultaneous ACL reconstruction. Therefore, we recommend ACL reconstruction in case of a combined injury of the ACL and a meniscus lesion which is suitable for repair. LEVEL OF EVIDENCE: Level V.

Management after acute injury of the anterior cruciate ligament (ACL), part 2: management of the ACL-injured patient.

PURPOSE: The aim of this consensus project was to create a treatment algorithm for the management of the ACL-injured patient which can serve as an aid in a shared decision-making process. METHODS: For this consensus process, a steering and a rating group were formed. In an initial face-to-face meeting, the steering group, together with the expert group, formed various key topic complexes for which various questions were formulated. For each key topic, a structured literature search was performed by the steering group. The results of the literature review were sent to the rating group with the option to give anonymous comments until a final consensus voting was performed. Sufficient consensus was defined as 80% agreement. RESULTS: During this consensus process, 15 key questions were identified. The literature search for each key question resulted in 24 final statements. Of these 24 final statements, all achieved consensus. CONCLUSIONS: This consensus process has shown that ACL rupture is a complex injury, and the outcome depends to a large extent on the frequently concomitant injuries (meniscus and/or cartilage damage). These additional injuries as well as various patient-specific factors should play a role in the treatment decision. The present treatment algorithm represents a decision aid within the framework of a shared decision-making process for the ACL-injured patient. LEVEL OF EVIDENCE: Level V.

Effect of shape and size of supraspinatus tears on rotator cuff strain distribution: an in vitro study.

BACKGROUND: The impact of the size and shape of a supraspinatus tear on the strain of the intact rotator cuff and the kinematics of the shoulder is still unknown. This, however, can be relevant when deciding whether surgical reconstruction is required to prevent an increase in a tendon defect. In this study, the effect of tear width and shape on rotator cuff strain and glenohumeral kinematics was evaluated during active abduction. METHODS: Twelve fresh-frozen cadaveric shoulders with intact rotator cuffs were used in this study. We created 50% and 100% wide (full-thickness) crescent-shaped (CS) tears (n = 6) and reverse L-shaped (rLS) tears (n = 6) in the supraspinatus tendon and measured strain and kinematics during active humeral elevation until 30°. RESULTS: Both tear shapes and sizes led to an increase in internal rotation, supraspinatus loading force, and superior translation of the humerus. For the 100% wide tear size, anterior translation was observed in the CS tear group, whereas in the rLS tear group, this translation occurred mainly in the posterior direction. Strain was higher in the infraspinatus during the first 25° of abduction in comparison with the supraspinatus tendon in both tear shape groups. An analysis of the anterior and posterior tear borders showed a higher strain concentration on the same side of the tear in the CS tear group with 50% and 100% wide tears. CONCLUSIONS: The influence of different tear shapes on translation in the anterior-posterior direction was evident as both CS and rLS tears led to an oppositely directed translation of the humeral head. The strain analysis showed a stress-shielding effect of the infraspinatus at the beginning of abduction. Therefore, special attention must be paid to correctly identify the tear extension and adequately reconstruct the rotator cuff footprint. Moreover, the constant location of maximum strain in the CS tear group may lead to an earlier progression than in the rLS tear group.

Drug-Membrane Interactions: Effects of Virus-Specific RNA-Dependent RNA Polymerase Inhibitors Remdesivir and Favipiravir on the Structure of Lipid Bilayers.

The two RNA-dependent RNA polymerase inhibitors remdesivir and favipiravir were originally developed and approved as broad-spectrum antiviral drugs for the treatment of harmful viral infections such as Ebola and influenza. With the outbreak of the global SARS-CoV-2 pandemic, the two drugs were repurposed for the treatment of COVID-19 patients. Clinical studies suggested that the efficacy of the drugs is enhanced in the case of an early or even prophylactic application. Because the contact between drug molecules and the plasma membrane is essential for a successful permeation process of the substances and therefore for their intracellular efficiency, drug-induced effects on the membrane structure are likely and have already been shown for other substances. We investigated the impact of remdesivir and favipiravir on lipid bilayers in model and cell membranes via several biophysical approaches. The measurements revealed that the embedding of remdesivir molecules in the lipid bilayer results in a disturbance of the membrane structure of the tested phospholipid vesicles. Nevertheless, in a cell-based assay, the presence of remdesivir induced only weak hemolysis of the treated erythrocytes. In contrast, no experimental indication for an effect on the structure and integrity of the membrane was detected in the case of favipiravir. Regarding potential prophylactic or accompanying use of the drugs in the therapy of COVID-19, the physiologically relevant impacts associated with the drug-induced structural modifications of the membrane might be important to understand side effects and/or low effectivities.

A semi-mechanistic dose-finding design in oncology using pharmacokinetic/pharmacodynamic modeling.

While a number of phase I dose-finding designs in oncology exist, the commonly used ones are either algorithmic or empirical model-based. We propose a new framework for modeling the dose-response relationship, by systematically incorporating the pharmacokinetic (PK) data collected in the trial and the hypothesized mechanisms of the drug effects, via dynamic PK/PD modeling, as well as modeling of the relationship between a latent cumulative pharmacologic effect and a binary toxicity outcome. This modeling framework naturally incorporates the information on the impact of dose, schedule and method of administration (e.g., drug formulation and route of administration) on toxicity. The resulting design is an extension of existing designs that make use of pre-specified summary PK information (such as the area under the concentration-time curve [AUC] or maximum serum concentration [Cmax ]). Our simulation studies show, with moderate departure from the hypothesized mechanisms of the drug action, that the performance of the proposed design on average improves upon those of the common designs, including the continual reassessment method (CRM), Bayesian optimal interval (BOIN) design, modified toxicity probability interval (mTPI) method, and a design called PKLOGIT that models the effect of the AUC on toxicity. In case of considerable departure from the underlying drug effect mechanism, the performance of the design is shown to be comparable with that of the other designs. We illustrate the proposed design by applying it to the setting of a phase I trial of a γ-secretase inhibitor in metastatic or locally advanced solid tumors. We also provide R code to implement the proposed design.

Oligometastatic disease in biochemical recurrence of prostate cancer: Prevalence on PSMA PET/CT and consecutive metastasis-directed therapy - Experience at a tertiary referral center.

AIM: The aim of our study was to address the prevalence of oligometastatic recurrent prostate cancer (PCa) on PSMA-PET and the associated practice of metastasis-directed therapy (MDT). Next, we aimed to determine a PSA threshold below which most patients had local and/or oligometastatic recurrence on PSMA-PET. METHODS: One hundred and ten consecutive patients with biochemical recurrence (BCR) after radical prostatectomy (RP) ± radiation were referred for 68Ga-PSMA-11 or 18F-DCFPyL PET/CT. We correlated the location and number of PSMA-positive lesions against the treatment choice after imaging. Detection rates were stratified by PSA levels at the time of PET/CT. The study design was monocentric retrospective. RESULTS: Thirty-four patients (30.9%) had a PSMA-negative scan, while 17 (15.5%) had local recurrence and 59 (53.6%) had metastatic recurrence on PSMA-PET. ROC analysis revealed a cut-off of ≤3 metastatic lesions on PSMA-PET for the steering of treatment decisions towards MDT rather than solely systemic therapy (AUC: 0.88). Defined as 3 or fewer metastatic lesions, oligometastatic recurrent PCa was found in up to 30% (33/110) of all patients. At PSA levels below 3.5 ng/ml, the rate of PSMA-positive disease that was locally confined or oligometastatic was 76% (45/59), dropping significantly to 29.4% (5/17) above this threshold (p<0.001) as polymetastatic findings became more frequent. CONCLUSION: The detection of ≤3 oligometastases on PSMA-PET encouraged the consecutive pursuit of MDT instead of systemic therapy alone. PSMA-PET predominantly captured patients at recurrence stages amenable to localized treatment when initiated at PSA levels below 3.5 ng/ml.

Osteogenic Differentiation of Human Adipose-Derived Stem Cells Seeded on a Biomimetic Spongiosa-like Scaffold: Bone Morphogenetic Protein-2 Delivery by Overexpressing Fascia.

Human adipose-derived stem cells (hADSCs) have the capacity for osteogenic differentiation and, in combination with suitable biomaterials and growth factors, the regeneration of bone defects. In order to differentiate hADSCs into the osteogenic lineage, bone morphogenetic proteins (BMPs) have been proven to be highly effective, especially when expressed locally by route of gene transfer, providing a constant stimulus over an extended period of time. However, the creation of genetically modified hADSCs is laborious and time-consuming, which hinders clinical translation of the approach. Instead, expedited single-surgery gene therapy strategies must be developed. Therefore, in an in vitro experiment, we evaluated a novel growth factor delivery system, comprising adenoviral BMP-2 transduced fascia tissue in terms of BMP-2 release kinetics and osteogenic effects, on hADSCs seeded on an innovative biomimetic spongiosa-like scaffold. As compared to direct BMP-2 transduction of hADSCs or addition of recombinant BMP-2, overexpressing fascia provided a more uniform, constant level of BMP-2 over 30 days. Despite considerably higher BMP-2 peak levels in the comparison groups, delivery by overexpressing fascia led to a strong osteogenic response of hADSCs. The use of BMP-2 transduced fascia in combination with hADSCs may evolve into an expedited single-surgery gene transfer approach to bone repair.

Seminal lipid profiling and antioxidant capacity: A species comparison.

On their way to the oocyte, sperm cells are subjected to oxidative stress, which may trigger the oxidation of phospholipids (PL). Applying MALDI-TOF MS, HPTLC and ESI-IT MS, we comparatively analyzed the PL compositions of semen and blood of species differing in their reproductive systems and types of nutrition (bull, boar, stallion, lion and man) with regard to the sensitivity to oxidation as well as the accumulation of harmful lyso-PL (LPL), transient products of lipid oxidation. In addition, the protective capacity of seminal fluid (SF) was also examined. The PL composition of erythrocytes and blood plasma is similar across the species, while pronounced differences exist for sperm and SF. Since the blood function is largely conserved across mammalian species, but the reproductive systems may vary in many aspects, the obtained results suggest that the PL composition is not determined by the type of nutrition, but by the relatedness of species and by functional requirements of cell membranes such as fluidity. Sperm motion and fertilization of oocytes require a rather flexible membrane, which is accomplished by significant moieties of unsaturated fatty acyl residues in sperm lipids of most species, but implies a higher risk of oxidation. Due to a high content of plasmalogens (alkenyl ether lipids), bull sperm are most susceptible to oxidation. Our data indicate that bull sperm possess the most effective protective power in SF. Obviously, a co-evolution of PL composition and protective mechanisms has occurred in semen and is related to the reproductive characteristics. Although the protective capacity in human SF seems well developed, we recorded the most pronounced individual contaminations with LPL in human semen. Probably, massive oxidative challenges related to lifestyle factors interfere with natural conditions.

Hydrogel-based autologous chondrocyte implantation leads to subjective improvement levels comparable to scaffold based autologous chondrocyte implantation.

PURPOSE: Scaffold-based autologous chondrocyte implantation is a well-established treatment for cartilage defects in the knee joint. Hydrogel-based autologous chondrocyte implantation using an in situ polymerizable biomaterial is a relatively new treatment option for arthroscopic cartilage defects. It is therefore important to determine if there are significant differences in the outcomes. The aim of this study is to compare the outcomes (using subjective parameters) of hydrogel-based autologous chondrocyte implantation (NOVOCART® Inject) with the outcomes of scaffold based autologous chondrocyte Implantation (NOVOCART® 3D) using biphasic collagen scaffold. METHODS: The data of 50 patients, which were paired with 25 patients in each treatment group, was analyzed. The main parameters used for matching were gender, number of defects and localization. Both groups were compared based on Visual Analogue Scale (VAS) and subjective IKDC scores, both of which were examined pre-operatively and after 6, 12 and 24 months. RESULTS: Significant benefits in both VAS and IKDC scores after 2 years of follow-up in both groups were found. Comparing the groups, the results showed that in the hydrogel-based autologous chondrocyte implantation group, significant changes in IKDC scores are measurable after 6 months, while it takes 12 months until they are seen in the scaffold based autologous chondrocyte group. CONCLUSION: Hydrogel-based autologous chondrocyte and scaffold based autologous chondrocyte show comparable improvements and significant benefits to the patients' subjective well-being after a 2-year-follow-up. LEVEL OF EVIDENCE: III.

CNGPLD: case-control copy-number analysis using Gaussian process latent difference.

MOTIVATION: Cross-sectional analyses of primary cancer genomes have identified regions of recurrent somatic copy-number alteration, many of which result from positive selection during cancer formation and contain driver genes. However, no effective approach exists for identifying genomic loci under significantly different degrees of selection in cancers of different subtypes, anatomic sites or disease stages. RESULTS: CNGPLD is a new tool for performing case-control somatic copy-number analysis that facilitates the discovery of differentially amplified or deleted copy-number aberrations in a case group of cancer compared with a control group of cancer. This tool uses a Gaussian process statistical framework in order to account for the covariance structure of copy-number data along genomic coordinates and to control the false discovery rate at the region level. AVAILABILITY AND IMPLEMENTATION: CNGPLD is freely available at https://bitbucket.org/djhshih/cngpld as an R package. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.